Researchers at Harvard's Wyss Institute have coaxed single strands of DNA to fit together like Lego bricks and form scores of complex three-dimensional shapes, including a teeny-tiny space shuttle. The technique, described in this week's issue of the journal Science, adds a new dimension to molecular construction and should help open the way for nanoscale medical and electronic devices.

"This is a simple, versatile and robust method," the study's senior author, Peng Yin, said in a news release.

The method starts with synthetic strands of DNA that take in just 32 nucleotides, or molecular bits of genetic code. These individual "bricks" are coded in a way that they fit together like Lego pegs and holes to form larger shapes of a specific design. A cube built up from 1,000 such bricks (10 by 10 by 10) measures just 25 nanometers in width. That's thousands of times smaller than the diameter of a single human hair.

The latest research builds upon work that the Wyss researchers detailed in May, which involved piecing together DNA strands to create two-dimensional tiles (including cute smiley faces). This time around, the strands were twisted in such a way that they could be interlocked, Lego-style. As any visitor to Legoland knows, such structures can get incredibly complex in the hands of a skilled builder.

Yin and his colleagues are still learning their building techniques. Fortunately, the bricks could be programmed to build themselves, with the aid of 3-D modeling software. Once the designs were set, the researchers synthesized strands with the right combinations of nucleotides — adenosine, thymine, cytosine and guanine — so that when they were mixed together in a solution, at least some of the bricks would form the desired design.

To demonstrate the method, 102 different 3-D shapes were created using a 1,000-brick template.

The Wyss researchers reported a wide variation in assembly success rate, or yield: Depending on the design, the yield ranged from 1 percent to 40 percent. That's roughly in the same range as the success rate for another method for molecular assembly, known as DNA origami. The origami method requires more custom work to design the "staples" to hold the DNA structures together, while the Lego-style method can rely more easily on a standard toolbox of DNA bricks.

In the future, DNA origami and DNA brick-building may be used together, said Kurt Gothelf, director of the Center for DNA Nanotechnology at Aarhus University in Denmark. "It is likely that a combination of the two methods will pave the way for making even larger structures in higher yields," Gothelf wrote in a commentary for Science.

Researchers say complex nanostructures could be used as smart drug delivery devices inside the human body, or as the components for microscopic electronic or photonic devices. It may look as if scientists are just playing around with smiley faces and toy shuttles, but a few years from now, DNA bricks will be no laughing matter.

Update for 3:30 p.m. ET: Peng Yin put me in touch with the Wyss Institute's Yonggang Ke, the lead researcher for the study, for an email Q&A. Here's an edited transcript:

Cosmic Log: I'm trying to visualize the self-assembly process. The shapes are designed using software, and that yields a recipe list for different strands that are synthesized, and then the various ingredients are combined to assemble themselves into the desired shapes?

Ke: "All the designs were done using software. First, a cubic '3-D canvas' model that contains 1,000 'voxels' was generated. [Each voxel represents an 8-base-pair connection between bricks.] Second, a list of a master collection of DNA strands (we ordered 4,455 strands) was generated based on the 3-D canvas. This master collection of strands covers all possibilities of shapes that can be designed from the 1,000-voxel 3-D canvas.Then we made 102 shapes using the software; each shape was designed by removing the unwanted voxels. At last, the software translates each shape to a recipe list of strands and sends the information to a robot for mixing the ingredients."

Q: Do you have to select 'good' structures of Lego blocks from undesirable or misshapen Lego structures?

A: "We didn't select the 'good' structures. That is why some structures' yields in the paper are so low. However, there are a few designed structures that failed self-assembly. They were mentioned in the supplementary material."

Q: I mentioned a couple of figures in the May report on your team's work with 2-D shapes: 12 to 17 percent yield, expected production of one desired shape per hour, $7,000 to synthesize a toolkit theoretically capable of producing 2 x 10^93 shapes. Do you have comparable figures for 3-D brick production?

A: "Yields of 3-D DNA-brick shapes were, on average, lower than 2-D DNA-brick shapes, but comparable to 3-D DNA origami structures. We saw yields varied from 1 percent to 40 percent, depending on the designs. The robot can make one 3-D shape per hour, which is similar to the pace for making 2-D shapes. The master collection of 4,455 strands cost about $11,000, but we can produce 2^1000 (about 10^301) potential shapes. The much larger number of potential shapes is due to the higher resolution in our 3-D brick design." [The size of the voxels is smaller, with just 8 base pairs per voxel.]

Q: Do you visualize combining the short-strand bricks into a completed structure, or building modular structures that are in turn built up into bigger structures (for example, that nanoscale space shuttle)? I assume this is where the combination of brick-building and origami might come in.

A: "Combining multiple DNA-brick structures to form a larger structure via 'hierarchical assembly' is certainly on our mind. I think we will inevitably need to combine many different DNA assembly methods, including DNA brick and DNA origami."

Q: It sounds as if you expect bricks as well as origami to be used together for nanostructure synthesis. Is this a change from the way you expected the field to develop in earlier days, or did you always expect that the two approaches would end up being used in combination?

A: "The ultimate goal of the DNA-brick technique and DNA origami is the same: making larger, more complex, more stable DNA structures. The two methods are also intrinsically connected.

"I borrow a paragraph from our paper: 'DNA origami can also be related to the brick framework, in which half of the bricks are concatenated into a long scaffold. ... The successes of constructions that use only short strands (as in bricks) and those that include a long scaffold (as in origami) together suggest a full spectrum of motif possibilities with strands of diverse lengths: Longer strands may provide better structural support, and shorter ones may provide finer modularity and features; the eclectic use of both may lead to the most rapid progression toward greater complexity.'

"We certainly expect the two techniques will complement each other."

Q: Do you feel as if this establishes a sufficient toolkit for nanostructure building, or are there other steps or techniques that will still be required? Are you working on additional techniques?

A: "Far from sufficient. The DNA-brick technique is great, compared with a lot of existing methods. It is modular, simple, and can make many complex shapes that were not accessible before. However, it is still not quite enough for many reasons. First of all, the structures are still only nanometer-scale objects. It will be great if we can get them to micrometer or even millimeter sizes. Second, we need to increase the stability of structures for many applications. Third, we want to be able to transfer the structural information to a lot of other materials (e.g. metals, carbon, silicon, protein…) to achieve more functions."

Q: Any more insight into the mechanism that leads to self-assembly?

A: "Right now we don't have any new hypotheses. A more important task for now is to search a reliable assay for studying the assembly mechanism."

Q: Is there any way to put an estimated time frame on applications for DNA structure assembly, or describe the potential applications?

A: "It is hard to predict a timetable. However, we believe we are really close to making high-profile real-world applications using DNA structures, considering the rapid growth of the field in recent years. Many papers have been published in the last couple of years, showing the potential for DNA structures in biophysical study, plasmonic devices, biosensoring, targeted delivery vehicle, etc.

Q: In May, we mentioned the potential for drug delivery or medical monitoring (for example, by nanomachines in the bloodstream). How does going from 2-D to 3-D change the outlook for applications? What are the big obstacles yet to be overcome?

A: "For some applications, 2-D DNA structures would suffice. However, for applications like drug delivery, going 3-D makes all the difference. A delivery vehicle/machine has to be a 3-D object that contains protective shell, recognition sites, etc. Note that we are at early stage of developing nano medical devices using DNA structures. The biggest obstacles in the near future are perhaps how to increase the stability of DNA structures in complex biological environments and how to observe the behaviors of the DNA structures in vivo."

Q: Anything to report on patenting these technologies or forming a venture to commercialize them?

A: "We have filed a provisional patent on the DNA-brick technique. We also have filed patents for other DNA techniques that we have invented in the past. We certainly expect that commercialization of these techniques will be a possibility in the future."

In addition to Yin and Ke, the authors of the Science paper, "Three-Dimensional Structures Self-Assembled From DNA Bricks," include Luvena L. Ong and William M. Shih. The work was supported by the Office of Naval Research, the Army Research Office, the National Institutes of Health, Wyss Institute and the National Science Foundation.